Isolated Idiopathic IHH

Impaired Pulsatile Secretion of LHRH
In absence of anosmia, the Kal gene is not involved, as demonstrated by Quinton et al.. However, familial histories have suggested the role of two different autosomal genes, as just described for non-X-linked Kal gene-related cases of KS. In these patients, partial LHRH neuronal migration is possible, leading to partial LHRH pulsatile secretion and partial pubertal development with primary amenorrhea (table 1).

Mutation of the LHRH Receptor Gene
In absence of response to the LHRH stimulation test and to pulsatile LHRH administration, a mutation of the LHRH receptor gene, which is located on chromosome 4, can be considered. Several autosomal recessive forms of congenital isolated IHH have been reported with such mutations. However, the phenotype seems to vary from partial to complete forms and the same molecular defect can exhibit different degrees of hypogonadism. Such mutations must be looked for in isolated IHH in cases of absent or impaired response to LHRH stimulation and/or to pulsatile LHRH administration.

Inactivating Mutation of FSH β Subunit

Only a handful of inactivating mutations of the FSH β gene located on Xp21 in women have been reported: one with partially developed secondary sex characteristics and two with primary amenorrhea.

Mutation of DAX1 Gene (Double Dose Adrenal Hypoplasia Congenital X-Linked Gene 1)

DAX1 is a transcriptional factor of the orphan nuclear receptor family which is involved in sexual differentiation and development of adrenal gland, hypothalamus, hypophysis and gonads. Mutations of this X-linked gene in males lead to adrenal congenital hypoplasia with neonatal adrenal insufficiency and deferred IHH revealed at adolescence. However, some cases of isolated IHH have been reported in women, which could represent a mild form of male HH associated with congenital adrenal hypoplasia. One observation with a homozygotic mutation in a woman with IHH and two other cases have been found by studying families of male cases and represent heterozygotic female forms with delayed puberty.

In fact, all these mutations on these different identified genes account for less than 20% of all IHH cases. Additional gene mutations will certainly be identified to help us to elucidate IHH syndromes and control of gonadotropin secretion.